August

Genomic analyses implicate noncoding de novo variants in congenital heart disease View Article Richter F, Morton SU, Kim SW, Kitaygorodsky A, Wasson LK, Chen KM, Zhou J, Qi H, Patel N, DePalma SR, Parfenov M, Homsy J, Gorham JM, Manheimer KB, Velinder M, Farrell A, Marth G, Schadt EE, Kaltman JR, Newburger JW, Giardini A, Goldmuntz E, Brueckner M, Kim R, Porter GA Jr, Bernstein D, Chung WK, Srivastava D, Tristani-Firouzi M, Troyanskaya OG, Dickel DE, Shen Y, Seidman JG, Seidman CE, Gelb BD. Nat Genet. 2020 Aug;52(8):769-777. doi: 10.1038/s41588-020-0652-z. Epub 2020 Jun 29. PMID: 32601476 Take Home Points: A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). In this National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Cardiac Genomics Consortium (PCGC) study of >13,000 patients with CHD utilizing whole-exome sequencing (WES) and chromosome microarrays rare, transmitted variants and DNVs in 8% of patients with sporadic CHD. CHD probands and their parents when compared to unaffected trios demonstrated a higher burden of DNVs in individuals with CHD. DNV burden was also observed in RNA-binding-protein regulatory sites. Comment from Dr. Shaji Menon (Salt Lake City, Utah), section editor of Pediatric Cardiology Journal Watch:   In this landmark study National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Cardiac Genomics Consortium (PCGC) recruited >13,000 patients and utilized whole-exome sequencing (WES) and chromosome microarrays to study CHD genetic architecture. The analyses identified damaging rare, transmitted variants and DNVs in 8% of patients with sporadic CHD (including 28% of syndromic and 3% of isolated CHD). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10−5). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. The study also demonstrated DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1–1.2, P = 8.8 × 10−5).

Protein-losing enteropathy and plastic bronchitis after the Fontan procedure View Article Varun J Sharma 1, Ajay J Iyengar 2, Diana Zannino 3, Thomas Gentles 4, Robert Justo 5, David S Celermajer 6, Andrew Bullock 6, David Winlaw 7, Gavin Wheaton 8, Luke Burchill 9, Rachael Cordina 10, Yves d'Udekem 11 J Thorac Cardiovasc Surg. 2020 Aug 12;S0022-5223(20)32359-X. doi: 10.1016/j.jtcvs.2020.07.107. Online ahead of print. PMID: 32928546;  DOI: 10.1016/j.jtcvs.2020.07.107 Take Home Points: Median time of onset of protein-losing enteropathy after Fontan is 5 years. Prevalence of protein-losing enteropathy and plastic bronchitis 30 years following after Fontan is 5%. Independent predictors for the risk of developing protein-losing enteropathy and plastic bronchitis were right ventricular morphology with HLHS, older age at Fontan, and prolonged pleural effusions after Fontan. Left ventricular morphology was protective. Freedom from death/transplantation after diagnosis of protein-losing enteropathy or plastic bronchitis at 5 and 10 years were 91% and 77% respectively. Comment from Dr. Shaji Menon (Salt Lake City, Utah), section editor of Pediatric Cardiology Journal Watch:   This is a retrospective analysis of 1561 patient from the Australia and New Zealand Fontan registry. A total of 55 patients with protein losing enteropathy/plastic bronchitis were studied. Their median age at the Fontan was 5.7 years, and time to onset after the Fontan for protein-losing enteropathy was 5.0 years and plastic bronchitis was 1.7 years. Independent predictors for developing protein-losing enteropathy/plastic bronchitis were right-ventricular morphology with hypoplastic left-heart syndrome (hazard ratio, 2.30; confidence interval, 1.12-4.74), older age at Fontan (hazard ratio, 1.13; confidence interval, 1.03-1.23), and pleural effusions after Fontan (hazard ratio, 2.43; confidence interval, 1.09-5.41); left-ventricular morphology was protective (hazard ratio, 0.36; confidence interval, 0.18-0.70). In the protein-losing enteropathy/plastic bronchitis population, freedom from death or transplantation after protein-losing enteropathy/plastic bronchitis diagnosis at 5, 10, and 15 years was 70% (confidence interval, 58-85), 65% (confidence interval, 51-83), and 43% (confidence interval, 26-73), respectively; only older age (hazard ratio, 1.23; confidence interval, 1.01-1.52) was an independent predictor.  Protein-losing enteropathy and plastic bronchitis remain severe complications of Fontan circulation specially in patients with a dominant right ventricle.  No significant improvement in transplant-free survival was noted in the current era. A quarter of patients require heart transplantation within a few years of diagnosis.

First-Degree Relatives Screening of Patients with Bicuspid Aortic Valve: Effectiveness and Feasibility in Pediatric Cardiology Daily Practice View Article Massardier C, Desroches F, Singbo N, Côté JM, Drolet C, Houde C, Vaujois L, Chetaille P. Pediatr Cardiol. 2020 Aug 26. doi: 10.1007/s00246-020-02423-x. Online ahead of print. PMID: 32851436 Take Home Points: Bicuspid aortic valve is the most common congenital heart disease with the prevalence of 1 to 2% in the general population and is now considered heritable. Echocardiographic screening of first-degree relatives of patients with bicuspid aortic valve is recommended. An autosomal dominant pattern of inheritance with incomplete penetrance is suspected. This study demonstrated a prevalence of 6% of bicuspid aortic valve in first-degree relatives (FDR). Comment from Dr. Shaji Menon (Salt Lake City, Utah), section editor of Pediatric Cardiology Journal Watch:   In this retrospective single center study from Canada, a total of 713 first-degree relatives of 213 consecutive index cases with the median age of 11 years were studied.  Bicuspid aortic valve (BAV) was found in 6.6% of first-degree relatives and 5.4% had aortic valve dysfunction.  A total of 2.9% subjects had ascending aorta dilation.  One third of first-degree relatives didn’t perform the screening. Screening was done in 482 (67.6%), prescribed but not done in 134 (19%), not prescribed in 92 (13%) and declined in 5 (1%) FDR. BAV was more frequent in men (68.5%) and most of cases had BAV with raphe (87.2%), largely represented by BAV type L-R (57.8%). By univariate analysis, no significant associations were found between screening positivity in first degree relatives and aortic valve morphology, aortic valve dysfunction or ascending aorta dilatation severity in index cases. The prevalence of BAV in first-degree relative was similar to prospective adult studies and supports actual guidelines in pediatric cardiology practice. Ascending aorta dilatation was rare in our young population. Exhaustiveness and additional burden to implement current guidelines remain a challenge in daily practice.